Reproductive Hormones; Male Reproductive Endocrinology

Chapters 16, 17

Hypothalamus

• GnRH– Peptide– Gonadotroph target – G-prot linked heptahelical transmembr

• Gq PLC pathway IP3-Ca, DAG-PKC-MAP kinase expression

of subunit common to FSH/LH

– Also opening of voltage gated Ca channels Ca influx

Anterior Pituitary• FSH, LH

– Glycoprot’s sim to TSH, hCG– Share common subunit– Hormone specific subunits

• LH subunit– Stim’d w/ GnRH @ higher freq’s, amp’s– Suppressed w/

• Androgens, progesterone (inhib freq GnRH pulses)

• Estrogens (directly @ pit)

• Testosterone estradiol in pit (via aromatase)

• FSH subunit– Highest when low freq GnRH pulses– Stim’d w/

• Activins incr’d FSH mRNA (autocrine)

– Suppressed w/• Sertoli cell inhibin B

• Testosterone/DHT

• Receptors on gonads– cAMP PKA act’n act’n enz’s for steroid

biosynth

Gonads

• Gametogenesis, hormonogenesis

• Sex steroids– Note: also prod’d by adrenal gland– Prior to puberty, basal levels secr’d

• Hypothal very sensitive

• Feedback inhibitory control of GnRH, LH/FSH

• Endocrine

• Testosterone major testes secretion

• Estradiol major ovarian secretion

Male Reproductive Anatomy (Human)

• Organs– Gonads: prod gametes, secrete hormones– Ducts: transport, store gametes– Accessory sex glands: support gametes

• Scrotum – Supports testes– Cremaster muscle– Temp reg’n

• Penis– Root, body, glans– Dilation arteries w/ parasymp stim’n

erection• Incr’d blood flow expansion blood sinuses

• Sinuses compress veins, trap entering blood

– Ejaculation: symp reflex• Peristalsis smooth muscle

• Propels semen from urethra to exterior

• Accessory sex glands– Seminal vesicles

• Secrete viscous, alkaline fluid (60% semen vol)

– Prostate gland• Secretes alkaline fluid (25% vol)

• Impt to sperm viability, motility

– Bulbourethral gland• Secretes mucus, alkaline fluid

• Semen– Sperm + secr’ns

• 120 x 106 sperm/mL

• Alkaline, nutrient secr’ns

– Vol: 2-6 mL– Seminalplasmin=antibiotic

Ducts• Urethra• Spermatic cord

– Testicular artery + autonomic nerves + veins + lymph vessels + cremaster muscle + vas deferens

• Vas deferens– Result of epidimi fusion– Stores mature sperm

• Ductus epididymis– Sperm maturation, storage

• Rete testis– Result of seminiferous tubule fusion– Gives rise to ducts

Testes

• Fibrous outer layer; connective tissue; lobules w/ seminiferous tubules

• Interstitium between seminiferous tubules contain Leydig cells (interstitial endocrinocytes)

Leydig Cells

• Testicular androgen production

• From cholesterol (liver)– Cycopentanoperhydophenanthrene nucleus

• Signal = LH @ plasma membr receptor– Heptahelical

Sex Steroid Biosynthesis

• Cholesterol pregnenolone – W/in Leydig cell mitoch matrix– Cat’d by P450scc

• Family of microsomal metab enz’s

• CYP genes

• 17-hydroxylase (P450C17) dominant in gonads sex steroids (fig.15.3)

• 3 hydroxylases/isomerases sensitive to FSH

Pregnenolone: produced directly from cholesterol, the precusor molecule for all C-18, C-19 and C-21 steroids 

Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake 

Cortisol:dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system

 

Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone 

Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics 

Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstral cycle, differentiation factor for mammary glands

• Most cholesterol extracell– Lipoproteins– Also de novo

• Pathway: via cAMP act’n PKA act’n steroid synthesis enzyme(s) – Rate limiting: delivery cholesterol to P450scc

in mitoch matrix– PKA-mediated induction steroidogenic acute

regulatory protein (StAR)

• StAR=Steroidogenic Acute Regulator protein– Synth induced w/ LH-receptor binding– Transiently inc’d into outer mitoch membr– Activates PBR

• PBR=Peripheral-type Benzodiazepine Receptor– Transmembr prot– “Mitochondrial porin” – Allows cholesterol mitoch matrix and

exposure to P450scc

• Major product=testosterone– Other androgens (fig.17.2), also estrogens

• DHT– Potent activator androgen receptor

• “Intracrine”

– 5 reductase cat’s synth• Almost all in periph tissues

• Impt to male embryonic dev’t + 2o sex char’s

– Also endocrine

• Aromatase– sER membrane anchored– CYPC19 gene

• Rel’d to CYP11A (mitoch P450scc)

• Rel’d to CYP1A1 (monooxygenase reg’d by aryl hydrocarbon receptor

• Diff tissues diff isozymes and/or diff promoters

– Assoc’d w/ cytP450 reductase

• Aromatase – cont’d– Steroids

• Effects ox’n, cleavage C19 Me Aromatization testosterone A ring Estradiol

– In males, adipose tissue has active aromatase• Correlation BMI/gynecomastia

– Impt to feedback control @ hypothal, ant pit

Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone 

Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics 

Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstral cycle, differentiation factor for mammary glands

• Plasma binding proteins nec in systemic circ’n– 40% bound to SHBG– 40% bound to albumin– 17% bound to other prot’s

• SHBG– Prod’d by liver– Homodimeric w/ testicular ABP

• Chromosome 17p12-13• Differ by oligosacch’s

– Higher affinity for testosterone over estrogens• Glycosylation incr’d by estrogens more SHBG more bound T; more free E2

• SHBG – cont’d– Glycosylation impt for recognition of cell

surface receptors• Can bind target tissues if not bound to ligand

– SHBG receptor• Presumed heptahelical transmembr

• Known cAMP/PKA mediation

– Binding SHBG enhancement cAMP effects w/ subsequent steroid binding

• Androgen receptor act’n

• Others

Seminiferous Tubules

• Formed from specialized epithelium• Epith = Sertoli cells (sustentacular cells)

– Support, nourish– Mediate hormonal effects– Control sperm movement– Secrete

• Fluid• Inhibin B

– Form blood-testis barrier

• FSH at Sertoli cells– Cell proliferation– Secretion

• Secretory prod’s of Sertoli’s– Inhibin

• At ant pit: inhibits FSH-b secr’n

• At Sertoli’s: antagonizes FSH prolif’n

– Transferrin (prot)• Shuttles Fe through blood-testis barrier

• Fe needed in mitoch cytochromes

Sperm Development in Seminiferous Tubule

Endocrinology of Seminiferous Tubules

• FSH binds Sertoli cells – Specific– Stim’s prod’n cyclic nucleotides – Does NOT stim synth, conversion of steroid

hormones– BUT enhances LH receptors in Leydig cells

• Book: w/ LH 3 hydroxysteroid dehydrogenase- isomerase activity

• With testosterone spermatogenesis @ puberty

• Still elucidating pathway

• Model: through cAMP ABP to localize testosterone– ABP=glycoprot sim to SHBG

• ABP testosterone complex impt– Androgen avail to developing sperm– Exocytosis lumen epididymis assist

maturation

Other Physio Functions of Reproductive Hormones

• Some sep’n androgenic vs. anabolic effects– Receptor differences?– Book: skel muscle androgen competition for glucocort

receptors

• Androgenic effects at muscle– Incr’d retention dietary N2 through prot synth Incr’d skeletal muscle mass

• Anabolic steroids: body mass effect, w/out masculinizing effects– Book: anabolic steroids ineffective w/ normal circ’ng

[testosterone]

Androgen Receptor

• At target cells• Nuclear protein family• High sequence identity w/ progesterone

receptor• Eight exons 3 functions

– N-terminal: transactivation + transcr’n reg’n– DNA binding domain (zinc fingers): DNA

recognition + dimerization w/ DNA binding– C-terminal: androgen binding